This invention relates to the field of organic chemistry, and more particularly to novel 1-(3,5-disubstituted-2,4,6-triiodophenyl)-3-(polyhydroxy-alkyl)urea compounds useful as non-ionic x-ray contrast media.
As is known, many 2,4,6-triiodobenzoic acid derivatives have been proposed and used as x-ray contrast agents. In general, it has been the practice to convert these compounds to salts, such as for example, the sodium and N-methylglucamine salts in order to render the compounds water-soluble and suitable for intravenous administration.
More recently, Almen et al. (U.S. Pat. No. 3,701,771, dated Oct. 31, 1972) have disclosed certain non-ionic N-(2,4,6-triiodobenzoyl)-sugar amines which are stated to be useful as x-ray contrast agents in the cerebrospinal cavities. In these compounds, a polyhydroxyalkyl chain is coupled to an iodoaromatic moiety in order to impart water solubility without resorting to ionic species. Certain of the non-ionic compounds disclosed in this patent were reported to be highly soluble in water while others were reported to have a medium or low water solubility.
Czechoslovakian Pat. No. 118,444 (published May 15, 1966) discloses, as x-ray contrast media, compounds of the formula: ##STR1## in which X is bromine or iodine and one of which may be hydrogen, Y is hydrogen, hydroxyl or methoxyl, R.sub.1 is hydrogen or an alkyl with 1-4 carbon atoms and R.sub.2 is carboxyalkyl with 2-6 carbon atoms, polyhydroxyalkyl with 4-6 carbon atoms or phenyl substituted in the 3- or 4- position by a carboxyl or sulfonamido group. However, it has been found that a representative compound of this class, namely, 3-[3-methoxy-2,4,6-triiodophenyl]-1-methyl-1-(D-gluco-2,3,4,5,6-pentahydro xyhexyl)urea, is insufficiently water-soluble (i.e., less than 1% soluble) for the purpose of determining its intravenous, intracerebral or intracisternal toxicity utilizing aqueous solutions of the compound.
In certain instances, non-ionic x-ray contrast media have been found to be less toxic than their ionic counterparts. This is believed to be due at least in part to the fact that the non-ionic compounds, being substantially non-ionized in aqueous solution, create less of an osmotic imbalance than do ionic compounds, i.e., non-ionic x-ray contrast media contribute only one molecular species per iodinated moiety as compared to ionic x-ray contrast media which contribute two or more species per iodinated moiety.
An interest has developed, therefore, in the synthesis of water-soluble, non-ionic x-ray contrast media possessing low toxicity and high iodine content for use in the x-ray visualization of areas of the body such as, for example, the cardiovascular and central nervous systems where high concentrations of contrast media are required in order to provide sufficient opacity.